Carbon electrophilic

Aryl and vinylic bromides and iodides react with the least substituted and most electrophilic carbon atoms of activated olefins, e.g., styrenes, allylic alcohols, a,p-unsaturated esters and nitriles. 

The use of oximes as nucleophiles can be quite perplexing in view of the fact that nitrogen or oxygen may react. Alkylation of hydroxylamines can therefore be a very complex process which is largely dependent on the steric factors associated with the educts. Reproducible and predictable results are obtained in intramolecular reactions between oximes and electrophilic carbon atoms. Amides, halides, nitriles, and ketones have been used as electrophiles, and various heterocycles such as quinazoline N-oxide, benzodiayepines, and isoxazoles have been obtained in excellent yields under appropriate reaction conditions. 

Quaternarj salts are obtained by alkylation of selenazole bases, the heterocyclic nitrogen atom playing the role of nucleophile with regard to the electrophilic carbon of the alkylating, agent. 

The reactions of ketenes or ketene equivalents with imines, discussed above, all involve the imine acting as nucleophile. Azetidin-2-ones can also be produced by nucleophilic attack of enolate anions derived from the acetic acid derivative on the electrophilic carbon of the imine followed by cyclization. The reaction of Reformatsky reagents, for example... 

Risaliti et al. (22), have shown that in the addition of the electrophilic olefins to the enamines of cyclohexanone, the formation of the less substituted enamine is favored when a bulky group is present at the electrophilic carbon atom. For instance, the reaction of (8-nitrostyrene with the morpholine enamine of cyclohexanone gave only the trisubstituted isomer (30) with the substituent in the axial orientation (23). The product on hydrolysis led to the ketone (31) to which erythro configuration was assigned on the grounds illustrated in Scheme 3 (24). 

However, when the bulky substituent is no longer present at the electrophilic carbon atom, the addition of the olefin to the morpholine enamine of cyclohexanone leads largely to the tetrasubstituted isomer. For instance the reaction of this enamine with phenyl vinyl sulfone gave a 1 3 mixture of... 

The preferred formation of the tetrasubstituted isomer with the olefin without any bulky substituent at the electrophilic carbon atom is undoubtedly due to the preponderance of that conformation of the dipolar intermediate in which the substituent is syn to the morpholine group, as shown in (41). The situation is, however, reversed in case of the olefin with... 

Risaliti et al. (2J) have also studied the addition of 2-nitropropene, which also lacks any substituent at the electrophilic carbon atom, to the morpholine enamine of cyclohexanone. The product, as expected, was the tetrasubstituted isomer, the formation of which may be envisioned via the transition state (42). 

Sn2 reactions proceed with inversion at the electrophilic carbon. This suggests that the nucleophile attacks from the backside of carbon, i.e., the side of carbon furthest away from the leaving group. 

Selective ether cleavage comes about during the substitution step, which obeys an Sn2 mechanism. Therefore, selective cleavage requires selective attack by Y on one of the electrophilic carbons in the protonated ether. Determine if selective attack is likely by examining the shape of the lowest-unoccupied molecular orbital (LUMO) in protonated ethyl propyl ether. Is this orbital larger near one carbon than the other If so, what product combination will result What other atom(s) contribute to the LUMO What would happen if 1 attacked this atom(s) ... 

Electrostatic interactions can guide alkylation under certain conditions. Examine the electrostatic potential map of the potassium enolate of ethyl acetoacetate. Is carbon or oxygen more electron rich Are electrostatic interactions likely to favor addition of oxygen or carbon Examine atomic charges and electrostatic potential maps for diethylsulfate, ethyl chloride, ethyl bromide and ethyl iodide, pay attention to the backside of the electrophilic carbon. Order the systems from most to least electron poor. Which reaction is most likely to be guided by electrostatics Least likely Can the experimental results be fully explained on this basis ... 

Examine atomic charges and electrostatic potential maps of these ions. Which ion has the most electron-poor electrophilic carbon Which has the least electrophilic carbon Is the variation in charge consistent with the observed reactivity patterns Explain. 

First, look at the reaction and identify the bonding changes that have occurred. In this case, a C—Br bond has broken and a C-C bond has formed. The formation of the C-C bond involves donation of an electron pair from the nucleophilic carbon atom of the reactant on the left to the electrophilic carbon atom ol CH Br, so we draw a curved arrow originating from the lone pair on the negatively charged C atom and pointing to the C atom of CH3Br. At the same time the C—C bond forms, the C-Br bond must break so that the octet rule is not violated. We therefore draw a second curved arrow from the C-Br bond to Br. The bromine is now a stable Br- ion. 

We won t study the details of this substitution reaction until Chapter 11 but for now can picture it as happening by the pathway shown in Figure 8.6. The nucleophilic acetylide ion uses an electron pair to form a bond to the positively polarized, electrophilic carbon atom of bromomethane. As the new C-C bond forms, Br- departs, taking with it the electron pair from the former C-Br bond and yielding propyne as product. We call such a reaction an alkylation because a new alkyl group has become attached to the starting alkyne. 

The nucleophilic acetylide anion uses its electron lone pair to form a bond to the positively polarized, electrophilic carbon atom of bromomethane. As the new C-C bond begins to form, the C-Br bond begins to break in the transition state. 

We ll defer a detailed discussion of the mechanisms of these reductions until Chapter 19. For the moment, we ll simply note that they involve the addition of a nucleophilic hydride ion ( H ) to the positively polarized, electrophilic carbon atom of the carbonyl group. The initial product is an afkoxide ion, which is protonated by addition of H 0+ in a second step to yield the alcohol product. 

The most common reaction of aldehydes and ketones is the nucleophilic addition reaction, in which a nucleophile, Nu , adds to the electrophilic carbon of the carbonyl group. Since the nucleophile uses an electron pair to form a new bond to carbon, two electrons from the carbon-oxygen double bond must move toward the electronegative oxygen atom to give an alkoxide anion. The carbonyl carbon rehybridizes from sp2 to sp3 during the reaction, and the alkoxide ion product therefore has tetrahedral geometry. 

O An electron pair from the nucleophile adds to the electrophilic carbon of the carbonyl group, pushing an electron pair from the C=0 bond onto oxygen and giving an alkoxide ion intermediate. The carbonyl carbon rehybridizes from sp2 to sp3. 

Like a carbonyl group, a nitrile group is strongly polarized and has an electrophilic carbon atom. Nitriles therefore react with nucleophiles to yield 5p2-hybridized imine anions in a reaction analogous to the formation of an sp3-hybridized alkoxide ion by nucleophilic addition to a carbonyl group. 

The intramolecular Michael addition11 of a nucleophilic oxygen to an a,/ -unsaturated ester constitutes an attractive alternative strategy for the synthesis of the pyran nucleus, a strategy that could conceivably be applied to the brevetoxin problem (see Scheme 2). For example, treatment of hydroxy a,/ -unsaturated ester 9 with sodium hydride furnishes an alkoxide ion that induces ring formation by attacking the electrophilic //-carbon of the unsaturated ester moiety. This base-induced intramolecular Michael addition reaction is a reversible process, and it ultimately affords the thermodynamically most stable product 10 (92% yield). 

In the first step, the fairly acidic proton on CIO of the red biladiene-ac salt 6 is abstracted and, even in solution in polar solvents, the salts are converted into the corresponding yellow bilatriene-u/ic salts 7. With a base such as piperidine, the salts 7 form the green bilatriene-a/>e free base. For further reaction to the porphyrin it is important that the salts 7 are oxidized to the bilatriene enamines 8 which cyclize via the electrophilic carbon of the terminal pyrrole ring by the loss of the leaving group X to 9. Porphin (10) is finally obtained by the loss of... 

Org. Chem. 1978, 43, 4207-4215 a related azepine formation through addition of N-unsubstituted azidirines to electrophilic carbon-carbon multiple bond systems such as acrylonitrile followed by aza-[3,3]-Claisen rearrangement was reported by Hassner (c) A. Hassner, R. D Costa,... 

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